Monoamine oxidase inhibition



Unit States Patent t 2,997,422 MONOAMINE OXIDASE INHIBITION Ralph E.Tedeschi, Lansdowne, Pa., assignor to Smith Kline & French Laboratories,Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Jan.9, 1959, Ser. No. 785,775

Claims. (Cl. 167-65) This invention relates to antidepressant andhypotensive compositions of trans 2-phenylcyclopropylamine, or themethyl or dimethylamino analogues and the method of treating depressedand hypertensive human beings with these compositions.

' Prior to the present invention the important advances in the treatmentof the mentally disturbed have been largely in the excited group ofpatients through the use of central nervous system depressant compoundscommonly referred to as transqui-lizers. These transquilizers providerelief in many cases for tense, anxious and overstimulated people. Alarge portion of the population of mental hospitals, however, consistsof depressed and regressed psychotics the opposite side of humantensions. There are also many ambulatory nonpsychotic depressed andregressed patients. These patients are either not responsivetotransquilizers or are aggravated by the use of these drugs. The usualtherapy for these patients is a stimulant or shock treatment, dependingupon the degree of depression. The need of a safe, effective compositionwith a minimum of side eifects for use in this area has been great.

The compositions of this invention exhibit potent mono amine oxidaseinhibitory properties. This inhibitory property of monoamine oxidase isassociated with antidepressant compounds, as for example, the iproniazidlike compounds. Results of the tryptamine potentiation test in rats,which is a reflection of amine oxidase inhibitory activity shows, thetrans isomer. of .2-phenylcyclopropylamine tobe significantly morepotent than the cis isomer. Combination studies in rabbits with trans2-phenylcyclopropylamine and reserpine in which signs of centralexcitement and pyrexia are observed indicate that this combination isdramatically more powerful than the iproniazid like compounds andreserpine combinations. This particular test procedure is an indicationof the activity of monoamine oxidase inhibition. In vitro testsmeasuring the rate of disappearance of serotonin when incubated with.whole rat brain homogenate again indicate that trans2-phenylcyclopropylamine is considerably more potent than iproniazidlike compounds as a monoamine oxidase inhibitor.

The composition in accordance with this invention is very useful as apsychic energizer, i.e., useful in treating depressed and regressedpsychotics as well as ambulatory nonpsychotic depressed patients. In thetreatment of this group of psychotics it induces antidepressant activitywith out any substantial amount of severe side effects such asjitteriness, excessive stimulation or increased tension observed fromclosely related compounds such as amphetamine. Also, unlike the relatedsympathominetic amines such amphetamine, ephedrine and epinephrine whichall cause -a rise in blood pressure in humans, the novel compositions ofthis invention unexpectedly brings about a lowering of blood pressureand demonstate hypotensive characteristics.

More specifically the. compositions of invention contain aphenylcyclopropylamine free base or a nontoxic acid addition saltthereof, the free base having the formula:

in accordance with this invention will also contain a nontoxicpharmaceutical carrier in addition to the medicinal agent.

The phenylcyclopropylamine of Formula I or a n0n-- toxic acid additionsalt there of will be present in an,

amount to produce antidepression and antihypertensive activity.Preferably the composition will contain the transZ-phenylcyclopropylamine ingredient in an amount of from about 5 mg. toabout 150 mg., advantageously from about 10 mg. to about 100 mg. perdosage unit.

The pharmaceutical carrier may be, for example, either a solid or aliquid. Exemplary of solid carriers are lactose, magnesium stearate,terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin oracacia. Exemplary of liquid,

carriers are peanut oil, olive oil, sesame oil, and water. Similarly,the carrier or diluent may include a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be em ployed. Thus, if asolid carrier is used, the preperation can be tabletted, placed on ahard gelatin capsule or in the form of a troche or lozenge. The amountof solid carrier will vary widely but preferably will be from about 25mg. to about 1 gm. If a liquid carrier is used, the preparation may bein the form of a soft gelatin capsule, placed in an ampule or in aliquid suspension.

The method in accordance with this invention comprises administeringinternally a compound of Formula I or. a nontoxic addition salt thereofadmixed with a pharmaceutical carrier, for example, any of the abovecompositions. The 2-phenylcyclopropylamine ingredient pref-' erably willbe, per unit, in an amount of from about 5 mg. to about 150 mg. andadvantageously from about 10 mg. to about 100 mg. The administration maybe parenterally or orally, the latter being the preferable route ofadministration. Advantageously equal doses will be administered one tofour times daily. Preferably the daily dosage will be from about 5 mg.to about 600 mg. and most advantageously from about 10 mg. to about 200mg.

the administration described above is carried out, both antidepressionand antihypertension results are obtained.

The trans isomer of 2-phenylcyclopropylamine is prepared by reactingstyrene with ethyl diazoacetate and the acid from hot water. The puretrans isomer comes Patented Aug. 22, 1961.

In their most advantageous forms, the compositions of active medicamentin pharmaceutical forms. When forming the ester, ethylZ-phenylcyclopropanecarboxylate. I J The resulting ester is hydrolyzedto the 2-phenylcyclo-j 3 out as crystalline material while the cisisomer stays in solution. The trans Z-phenylcyclopropanecarboxylic acidis then reacted with thionyl chloride to form the acid chloride which isthen successively treated with sodium azide and subjected to the curtiusdegradation. The isocyanate formed by this procedure is hydrolyzedreadily to the Z-phenylcyclopropylamine or reduced to the secondarymonomethylamine. The dimethylamino derivatives are obtained bymethylation of the primary amine with a mixture of aqueous formaldehydeand formic acid.

Preferably the hydrochloride salt of the trans 2-phenylcyclopropylamineis used, however, either the base itself or a nontoxic, pharmaceuticallyacceptable acid addition salt of the base may be used, such as the saltderived from sulfuric, nitric, phosphoric, citric, acetic, lactic,mandelic, salicylic, tartaric, ethanedisulfonic, sulfamic,acetylsalicylic, succinic, fuman'c, maleic, hydrobromic, benzoic andlike nontoxic acids. The salts are best prepared by reacting the freebase with a stoichiometric amount of the desired organic or inorganicacid in a suitable solvent such as ethyl acetate-ether solution,ethanol, acetone, water or various combinations of solvents.

The invention will be further clarified by the following specificexamples of preparations in accordance with this invention.

Example I -A solution containing 167 g. of stabilized styrene and 183 g.of ethyl diazoacetate is cooled to C. and dropped into 83.5 g. ofstyrene with stirring, in a dry nitrogen atmosphere, at 125l35 C. Thisproduced the ester ethyl Z-phenylcyclopropanecarboxylate.

A solution of the above ester (207.8 g.) and 64.5 g. of sodium hydroxidein 80 cc. of water and 600 cc. of ethanol is refluxed for 9 hours. The,carboxylic acid of 2-phenylcyclopropane is liberated with 200 cc. ofconcentrated hydrochloric acid. The Z-phenylcyclopropanecarboxylic acidcontains 3 to 4 parts of the trans isomer to 1 part of the cis isomer.The acid is recrystallized from hot Water. The pure trans isomer comesout as crystalline material (solid) while the cis isomer stays insolution.

A solution of 4.62 g. of 2-phenylcyclopropanecarboxylic acid in 15 cc.of dry benzene is refluxed with 4 cc. of thionyl chloride for fivehours, the volatile liquids are removed and the residue once, moredistilled with benzene. Fractionation of the residue yields the carbonylchloride of 2-phenylcyclopropane.

A mixture of 15 g. of technical sodium azide and 50 cc. of dry tolueneis stirred and warmed and a solution of g. ofZ-phenylcyclopropanecarbonyl chloridev in 50 cc. of dry toluene is addedslowly. Inorganic salts are filtered and washed well with dry benzeneand the solvents are removed under reduced pressure. The residualisocyanate is a clear red oil of characteristic. odor. It is cooled to10 C. and treated cautiously with 100 cc. of- 55 hydrochloric acid.After most of the evolution of carbon dioxide has subsided the mixtureis refluxed for 13 hours the cooled solution is diluted with 75 cc. ofwater and extracted with three 50 cc. portions of ether. The acid.solution is evaporated under reduced pressure with occasional additionsof toluene to reduce foaming,

The almost dry residue is cooled to 0 C. and made strongly alkaline witha 50% potassium hydroxide solution. The amine is extracted into severalportions of ether, dried over potassium hydroxide, the solvent removed,and the base fractionated.

Conversion to the hydrochloride proceeds best in ethyl acetate-ethersolution. The crude salt is recrystallized by dissolving it in the leastamount of cold methanol and precipitation with absolute ethyl acetateand ether. The colorless needles thus obtained have a melting point of15l-154 C.

Example 2 A solution of'5 g. of trans 2-phenylcyclopropylamine('asprepared in Example 1) and 4.3 g. of benzaldehyde in 10 cc. ofabsolute ethanol is refluxed for three hours. The solvent is removed invacuo and the benzal derivative distilled.

A mixture of 6 g. of trans 2-phenylcyclopropylbenzalamine and 7.7 g. ofmethyl iodide is heated in a sealed tube at 95 C. for seven hours. Thereaction product is boiled with 75 ml. of 95% ethanol for four hours,the solvent removed in vacuo, the base liberated with 40% potassiumhydroxide solution and extracted with ether. The dried ether extract isevaporated and the residue distilled to give trans2-phenylcyclopropylmethylamine.

An ethereal solution of the free base treated with anhydrous hydrogenchloride gas yields the hydrochloride salt.

Example 3 cylcopropylamine in 13.2 g. of formic acid and the mixture isrefluxed for 1.4 hours. The cooled reaction mixture is treated with 5.5cc. of concentrated hydrochloric acid, the solution is evaporated invacuo. The residue is made alkaline with 50% potassium hydroxidesolution and the solution extracted with ether. The dried ether extractsare evaporated to give the residual trans2-phenylcyclopropyldimethylamine.

The free base dissolved in ethyl acetate is added to a solution ofmandelic acid in ethanol. Concentration of the resulting solution andcooling yields the crystalline trans 2-phenylcyclopropyldimethylaminemandelate.

Example 4 Ingredients: Amounts, mg.

Trans z-phenylcyclopropylamine hydrochlo ride 75.00 Magnesium stearate2.00 Lactose 130.00

The above powders are thoroughly mixed and filled into a #2 hard gelatincapsule.

Example 5 Ingredients: Amounts, mg.

Trans Z-phenylcyclopropylmethylamine hydrochloride 25.00 Magnesiumstearate 2.00 Lactose 2.65.00

The ingredients are mixed and filled into a #2 hard gelatin capsule.

Example 6 Ingredients: Amounts, mg. Trans Z-phenylbyclopmpylamine 50.00Calcium sulfate,v dihydrate (terra alba).. 125.00 Sucrose 25.00 Starch15.00 Talc. 5.00 Stearic acid 3.00

Example 7 Ingredients: Amounts, mg.

Trans 2-phenylcyclopropyldimethylamine sulfate, 5.00" Lactose 250.00Starch 13.00 Talc 5;00

Magnesium stearate 2.50

The lactose and trans 2-phenylcyclopropylamine sulfate are mixed andgranulated with hot gelatin. The magnesium stearate, talc and starch areadmixed according to procedure of Example 4 and compressed into a Theingredients are mixed and filled into a #2 hard gelatin capsule.

Example 9 Ingredients: Amounts, mg. Trans 2-phenylcyclopropylaminemaleate.. 50.00 Peanut oil 225.00

The ingredients are mixed to a thick slurry and filled into a softgelatin capsule.

Example 10 Ingredients: Amounts, gms.

Trans 2-phenylcyclopropylamine hydrochloride 2.0 Sodium ch 0.375

Water for injection, q.s., 100.00 ml.

The salts are dissolved in part of the water and then the volume isbrought up to 100 ml. The solution is then filtered through a selasfilter, filled into ampuls and autoclaved.

What is claimed is:

1. The method of producing monoamine oxidase inhibition which comprisesinterally administering a dosage unit of from about 5 mg. to about 150mg. of a compound selected from the group consisting of the free baseand its nontoxic, pharmaceutically acceptable, acid addition salts, saidfree base having the formula:

in which R and R are members selected from the group consisting ofhydrogen and methyl.

2. The method of producing monoamine oxidase inhibition which comprisesinternally administering a daily dosage regimen of from about 5 mg. toabout 600 mg. of a compound selected from the group consisting of thefree base and its nontoxic, pharmaceutically acceptable, acid additionsalts, said free base having the formula:

OH: H

in which R and R are members selected from the group consisting ofhydrogen and methyl.

3. The method of producing monoamine oxidase inceutically acceptable,acid ddition salts, said free base having the formula:

in which R, and R are members selected from the group consisting ofhydrogen and methyl.

4. The method of producing monoamine oxidase inhibition which comprisesorally administering a daily dosage regimen of from about 10 mg. toabout 200 mg. of a compound selected from the group consisting of thefree base and its nontoxic, pharmaceutically acceptable, acid additionsalts, said free base having the formula:

in which R and R are members selected from the group consisting ofhydrogen and methyl.

5. The method of producing monoamine oxidase inhibition which comprisesorally administering a daily dosage regimen of from about 10 mg. toabout 200 mg. of a member selected from the group consisting of trans-2-phenylcyclopropy1amine and its nontoxic, pharmaceutically acceptable,acid addition salts.

6. The method in accordance with claim 5 characterized in that saidmember is essentially free from its cis isomer.

7. The method of producing monoamine oxidase inhibition which comprisesorally administering a daily dosage regimen of from about 1 0 mg. toabout 200 mg. of trans-2-phenylcyclopropylamine sulfate.

8. The method of producing monoamine oxidase inhibition which comprisesorally administering a daily dosage regimen of from about 10 mg. toabout 200 mg. of a member selected from the group consisting of trans-2-phenylcyclopropyldimethylamine and its nontoxic, pharmaceuticallyacceptable, acid addition salts.

9. The method in accordance with claim 8 characterized in that saidmember is trans-2-phenylcyclopropyldimethylamine sulfate.

10. The method of producing monoamine oxidase inhibition which comprisesorally administering to depressed patients from one to four times dailya dosage unit of from about 5 mg. to about mg. of a compound selectedfrom the group consisting of trans-2-phenylcyclopropylamine and itsnontoxic, pharmaceutically acceptable, acid addition salts.

References Cited in the file of this patent UNITED STATES PATENTS ZoerenAug. 29, 1950 OTHER REFERENCES of Science, vol. 80, (Result of confer-

1. THE METHOD OF PRODUCING MONOAMINE OXIDASE INHIBITION WHICH COMPRISESINTERALLY ADMINISTERING A DOSAGE UNIT OF FROM ABOUT 5 MG. TO ABOUT 150MG. OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE FREE BASEAND ITS NONTOXIC, PHARMACEUTICALLY ACCEPTABLE, ACID ADDITION SALTS, SAIDFREE BASE HAVING THE FORMULA: